Reanalysis of "Long non‑coding RNA lung cancer‑associated transcript 1 regulates ferroptosis via microRNA‑34a‑5p‑mediated GTP cyclohydrolase 1 downregulation in lung cancer cells." by Tai, F. et al., Int J Oncol, 2024

Tai, F., Zhai, R., Ding, K., Zhang, Y., Yang, H., Li, H., Wang, Q., Cao, Z., Ge, C., Fu, H., Xiao, F., & Zheng, X. (2024). Long non‑coding RNA lung cancer‑associated transcript 1 regulates ferroptosis via microRNA‑34a‑5p‑mediated GTP cyclohydrolase 1 downregulation in lung cancer cells.. Int J Oncol, 64(6), .

Abstract

In this study, Tai et al. [1] profiled A549 cells treated with DMSO, RSL3 alone, or co-treated with Fer-1 for 24h to further our understanding of ferroptosis-associated genes in non-small cell lung cancer (NSCLC). The reanalysis of this dataset include a comprehensive RNA-seq analysis pipeline which begins with dimensionality reduction using UMAP [2], PCA [3], and t-SNE [4] to visualize sample distributions. This is followed by a clustergram heatmap to show expression patterns across samples. Differential gene expression analysis is performed for each control and perturbation pair, and the resulting gene signatures are then subjected to enrichment analysis using Enrichr [5, 6, 7]. Furthermore, transcription factor analysis of the gene signatures is conducted using ChEA3 [8]. Finally, the analysis incorporates drug match prediction using L2S2 [9] and DRUG-seqr [10] to identify both FDA-approved and non-FDA-approved compounds that can reverse or mimic the observed gene expression changes. Results are presented as tables and bar charts to facilitate interpretation.

This abstract was generated with the assistance of Gemini 2.0 Flash.

Methods

RNA-seq alignment

Gene count matrices were obtained from ARCHS4 [11], which preprocessed the raw FASTQ data using the Kallisto [12] and STAR [] pseudoalignment algorithm.

Gene matrix processing

The raw gene matrix was filtered to remove genes that do not have an average of 3 reads across the samples. It was then quantile, log2, and z-score normalized. A regex-based function was used to infer whether individual samples belong to a “control” or a “perturbation” group by processing the metadata associated with each sample.

Dimensionality Reduction Visualization

Three types of dimensionality reduction techniques were applied on the processed expression matrices: UMAP[2], PCA[3], and t-SNE[4]. UMAP was calculated by the UMAP Python package and PCA and t-SNE were calculated using the Scikit-Learn Python library. The samples were then represented on 2D scatterplots.

Clustergram Heatmap

As a preliminary step, the top 1000 genes exhibiting most variability were selected. Using this new set, clustergram heatmaps were generated. Two versions of the clustergram exist: an interactive one generated by Clustergrammer [13] and a publication-ready alternative.

Differentially Expressed Genes Calculation and Volcano Plot

Differentially expressed genes between the control and perturbation samples were calculated using Limma Voom [14]. The logFC and -log10p values of each gene were visualized as a volcano scatterplot. Upregulated and downregulated genes were selected according to this criteria: p < 0.05 and |logFC| > 1.0.

Enrichr Enrichment Analysis

The upregulated and down-regulated sets were separately submitted to Enrichr [5, 6, 7]. These sets were compared against libraries from ChEA [8], ARCHS4 [12], Reactome Pathways [15], MGI Mammalian Phenotype [16], Gene Ontology Biological Processes [17], GWAS Catalog [18], KEGG [19, 20, 21], and WikiPathways [22]. The top matched terms from each library and their respective -log10p values were visualized as barplots.

Chea3 Transcription Factor Analysis

The upregulated and down-regulated sets were separately submitted to Chea3 [8]. These sets were compared against the libraries ARCHS4 Coexpression [12], GTEx Coexpression [23], Enrichr [5, 6, 7], ENCODE ChIP-seq [24, 25], ReMap ChIP-seq [26], and Literature-mined ChIP-seq. The top matched TFs were ranked according to their average score across each library and represented as barplots.

L2S2 and Drug-seqr drug analysis

The top 500 up and downregulated sets were submitted simulataneously to identify reverser and mimicker molecules, both FDA and non-FDA approved, from the L2S2 [9] and Drug-seqr [10] databases. The top matched molecules were compiled into tables and visualized as barplots.

GSM7902660 GSM7902661 GSM7902662 GSM7902663 GSM7902664 GSM7902665 GSM7902666 GSM7902667 GSM7902668
TSPAN6 507 530 530 581 536 517 566 579 619
TNMD 0 0 0 0 0 0 0 0 0
DPM1 445 441 458 434 432 383 459 462 466
SCYL3 221 230 232 261 238 226 238 297 245
C1ORF112 554 558 634 483 580 519 616 632 633

table 1: This is a preview of the first 5 rows of the raw RNA-seq expression matrix from GSE247883.

Results

Dimensionality Reduction

UMAP

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Figure 1: This figure displays a 2D scatter plot of a UMAP decomposition of the sample data. Each point represents an individual sample, colored by its experimental group.

PCA

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Figure 2: This figure displays a 2D scatter plot of a PCA decomposition of the sample data. Each point represents an individual sample, colored by its experimental group.

t-SNE

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Figure 3: This figure displays a 2D scatter plot using a t-SNE decomposition of the sample data. Each point represents an individual sample, colored by its experimental group.

Clustergram Heatmaps

Figure 4: The figure contains an interactive heatmap displaying gene expression for each sample in the RNA-seq dataset. Every row of the heatmap represents a gene, every column represents a sample, and every cell displays normalized gene expression values. The heatmap additionally features color bars beside each column which represent prior knowledge of each sample, such as the tissue of origin or experimental treatment.

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Figure 5: this figure is a clustergram produced with the graphing library Plotly. It sacrifices some interactivity for a more polished look.

Differentially Expressed Genes Calculation and Volcano Plots

logFC AveExpr t P.Value adj.P.Val B
gene_symbol
GRAMD1B 0.74 8.93 33.03 5.954069e-17 9.013920e-13 29.05
SLC7A11 1.01 9.21 32.92 6.302118e-17 9.013920e-13 29.07
SQSTM1 0.59 9.05 27.02 1.745352e-15 1.328005e-11 25.81
TXNRD1 0.40 10.02 26.92 1.856959e-15 1.328005e-11 25.62
AKR1C3 2.11 5.73 23.36 1.984020e-14 1.135098e-10 20.59

Table 2: This is a preview of the first 5 rows of the differentially expressed gene table calculated by Limma Voom.

logFC AveExpr t P.Value adj.P.Val B
gene_symbol
GRAMD1B 0.96 9.04 42.15 3.314248e-19 6.153087e-15 34.21
EGFR 0.39 11.97 41.52 4.301955e-19 6.153087e-15 33.20
TXNRD1 0.60 10.11 37.63 2.417543e-18 1.855332e-14 32.29
GPRC5A 0.84 9.50 37.32 2.786586e-18 1.855332e-14 32.21
SLC7A11 1.25 9.32 37.00 3.242907e-18 1.855332e-14 32.05

Table 3: This is a preview of the first 5 rows of the differentially expressed gene table calculated by Limma Voom.

cells dmso h rep-vs-cells rsl fer h rep

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Figure 6: The figure contains an interactive scatter plot which displays the log2-fold changes and statistical significance of each gene calculated by performing a differential gene expression analysis for the comparison cells dmso h rep-vs-cells rsl fer h rep. Every point in the plot represents a gene. Red points indicate significantly up-regulated genes, blue points indicate down-regulated genes.

cells dmso h rep-vs-cells rsl h rep

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Figure 7: The figure contains an interactive scatter plot which displays the log2-fold changes and statistical significance of each gene calculated by performing a differential gene expression analysis for the comparison cells dmso h rep-vs-cells rsl h rep. Every point in the plot represents a gene. Red points indicate significantly up-regulated genes, blue points indicate down-regulated genes.

Enrichr: Enrichment Analysis

Upregulated Set

cells dmso h rep-vs-cells rsl fer h rep

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Figure 8: This figure contains several barplots depicting enrichment analysis results on the upregulated gene set. Each barplot corresponds to an individual library from Enrichr, and the top matching terms by p-value are depicted in each. Statistically significant terms are represented as red bars while others are represented as gray. Access your Enrichment results here: https://amp.pharm.mssm.edu/Enrichr/enrich?dataset=37688fa2cdb8fd824ac139fe44ac4f5a

cells dmso h rep-vs-cells rsl h rep

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Figure 9: This figure contains several barplots depicting enrichment analysis results on the upregulated gene set. Each barplot corresponds to an individual library from Enrichr, and the top matching terms by p-value are depicted in each. Statistically significant terms are represented as red bars while others are represented as gray. Access your Enrichment results here: https://amp.pharm.mssm.edu/Enrichr/enrich?dataset=f46cc8b3b6124d04b1e2ec6f647579ea

Downregulated Set

cells dmso h rep-vs-cells rsl fer h rep

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Figure 10: This figure contains several barplots depicting enrichment analysis results on the upregulated gene set. Each barplot corresponds to an individual library from Enrichr, and the top matching terms by p-value are depicted in each. Statistically significant terms are represented as red bars while others are represented as gray. Access your Enrichment results here: https://amp.pharm.mssm.edu/Enrichr/enrich?dataset=f46cc8b3b6124d04b1e2ec6f647579ea

cells dmso h rep-vs-cells rsl h rep

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Figure 11: This figure contains several barplots depicting enrichment analysis results on the upregulated gene set. Each barplot corresponds to an individual library from Enrichr, and the top matching terms by p-value are depicted in each. Statistically significant terms are represented as red bars while others are represented as gray. Access your Enrichment results here: https://amp.pharm.mssm.edu/Enrichr/enrich?dataset=f46cc8b3b6124d04b1e2ec6f647579ea

CHEA3: Transcription Factor Enrichment Analysis

Upregulated Set

cells dmso h rep-vs-cells rsl fer h rep

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Figure 12: Horizontal bar chart, y-axis represents transcription factors. Displays the top ranked transcription factors for the upregulated set according to their average integrated scores across all the libraries.

cells dmso h rep-vs-cells rsl h rep

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Figure 13: Horizontal bar chart, y-axis represents transcription factors. Displays the top ranked transcription factors for the upregulated set according to their average integrated scores across all the libraries.

Downregulated Set

cells dmso h rep-vs-cells rsl fer h rep

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Figure 14: Horizontal bar chart, y-axis represents transcription factors. Displays the top ranked transcription factors for the upregulated set according to their average integrated scores across all the libraries.

cells dmso h rep-vs-cells rsl h rep

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Figure 15: Horizontal bar chart, y-axis represents transcription factors. Displays the top ranked transcription factors for the upregulated set according to their average integrated scores across all the libraries.

L2S2 and DRUG-seqr: Reverser and Mimicker Drugs

Reverser Results

cells dmso h rep-vs-cells rsl fer h rep

l2s2_fda

perturbation term pvalueReverse adjPvalueReverse oddsRatioReverse reverserOverlap approved count
0 trametinib PBIOA004_XC.L10_24H_K06_trametinib_2.22uM up 2.15e-10 1.64e-05 3.47e+00 37 True 1552
1 selumetinib ASG003_XC.P909_24H_E04_selumetinib_10uM up 2.15e-10 1.64e-05 3.47e+00 37 True 2242
2 afatinib ASG003_XC.P914_24H_M20_afatinib_1.11uM up 8.27e-10 3.22e-05 3.37e+00 36 True 2348
3 acyclovir REP.A008_MCF7_24H_E06_acyclovir_0.04uM up 8.27e-10 3.22e-05 3.37e+00 36 True 290
4 selumetinib REP.A015_A375_24H_E19_selumetinib_10uM up 8.27e-10 3.22e-05 3.37e+00 36 True 2242
5 trametinib PBIOA004_XC.R10_24H_K04_trametinib_20uM up 8.27e-10 3.22e-05 3.37e+00 36 True 1552
6 dinoprostone FIBR026_MCLF141SZ_6H_M12_dinoprostone_4uM up 8.27e-10 3.22e-05 3.37e+00 36 True 138
7 selumetinib ASG003_XC.P091_24H_E05_selumetinib_1.11uM up 3.07e-09 7.16e-05 3.27e+00 35 True 2242
8 selumetinib LJP006_A549_24H_M07_selumetinib_10uM up 3.07e-09 7.16e-05 3.27e+00 35 True 2242
9 trametinib ASG003_XC.P911_24H_N18_trametinib_0.12uM up 3.07e-09 7.16e-05 3.27e+00 35 True 1552
10 thioridazine CPC006_HCC515_6H_G23_thioridazine_10uM up 3.07e-09 7.16e-05 3.27e+00 35 True 1444
11 selumetinib LKCP001_A549_24H_J10_selumetinib_10uM up 3.07e-09 7.16e-05 3.27e+00 35 True 2242
12 trametinib PBIOA004_XC.L10_24H_K04_trametinib_20uM up 1.11e-08 1.47e-04 3.17e+00 34 True 1552
13 chlorotrianisene PAC003_U2OS_6H_F14_chlorotrianisene_10uM up 1.11e-08 1.47e-04 3.17e+00 34 True 28
14 trametinib ASG003_XC.P909_24H_N18_trametinib_0.12uM up 1.11e-08 1.47e-04 3.17e+00 34 True 1552
15 trametinib ASG002_NCIH1573_24H_G09_trametinib_0.12uM up 1.11e-08 1.47e-04 3.17e+00 34 True 1552
16 famotidine PAC004_U2OS_6H_B06_famotidine_10uM up 1.11e-08 1.47e-04 3.17e+00 34 True 332
17 trametinib LCP001_MCF10A.WT_3H_D16_trametinib_10uM up 1.11e-08 1.47e-04 3.17e+00 34 True 1552
18 thalidomide CPC006_A549_6H_E14_thalidomide_10uM up 1.11e-08 1.47e-04 3.17e+00 34 True 850
19 dasatinib LJP007_HT29_24H_G14_dasatinib_3.33uM up 1.11e-08 1.47e-04 3.17e+00 34 True 3026

Table 4: Ranked FDA-approved LINCS L1000 signatures predicted to reverse the uploaded geneset.

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Figure 16: barplot representation depicting the -log10p values of the top FDA-approved l2s2_fda reversers. Red bars represent statistically significant results; otherwise gray.

l2s2_all

perturbation term pvalueReverse adjPvalueReverse oddsRatioReverse reverserOverlap approved count
0 PD-0325901 LGR001_XC.L100.L_96H_H06_PD-0325901_0.04uM up 1.57e-13 2.63e-07 3.98e+00 42 False 3630
1 BRD-K85051645 CPC007_MCF7_6H_M06_BRD-K85051645_10uM up 3.10e-12 2.60e-06 3.78e+00 40 False 58
2 BIIB-021 REP.A016_MDAMB231_24H_D22_BIIB-021_0.37uM up 1.31e-11 4.41e-06 3.67e+00 39 False 346
3 PD-0325901 LGR001_XC.L100.L_120H_H01_PD-0325901_10uM up 1.31e-11 4.41e-06 3.67e+00 39 False 3630
4 XL-888 ASG003_XC.P908_24H_L14_XL-888_1.11uM up 1.31e-11 4.41e-06 3.67e+00 39 False 878
5 PD-0325901 LGR001_XC.L100.M_72H_H02_PD-0325901_3.33uM up 5.40e-11 8.24e-06 3.57e+00 38 False 3630
6 XL-888 ASG003_XC.P907_24H_L14_XL-888_1.11uM up 5.40e-11 8.24e-06 3.57e+00 38 False 878
7 PD-0325901 LGR001_XC.L100.M_72H_H05_PD-0325901_0.125uM up 5.40e-11 8.24e-06 3.57e+00 38 False 3630
8 BRD-K82710617 MOA001_A549_24H_G05_BRD-K82710617_10uM up 5.40e-11 8.24e-06 3.57e+00 38 False 16
9 SH3BP5 up XPR014_U251MG.311_96H_E11_SH3BP5 up 5.40e-11 8.24e-06 3.57e+00 38 False 150
10 BRD-K26347562 MOA001_A549_24H_K21_BRD-K26347562_10uM up 5.40e-11 8.24e-06 3.57e+00 38 False 196
11 trametinib PBIOA004_XC.L10_24H_K06_trametinib_2.22uM up 2.15e-10 1.64e-05 3.47e+00 37 True 1552
12 vemurafenib LJP005_MDAMB231_24H_C16_vemurafenib_0.37uM up 2.15e-10 1.64e-05 3.47e+00 37 False 1862
13 BRD-K00824317 PAC004_U2OS_6H_B09_BRD-K00824317_4uM up 2.15e-10 1.64e-05 3.47e+00 37 False 40
14 AZ-628 LJP001_MDAMB231_24H_J12_AZ-628_0.08uM up 2.15e-10 1.64e-05 3.47e+00 37 False 1618
15 TNFRSF1A up XPR028_A549.311_96H_C03_TNFRSF1A up 2.15e-10 1.64e-05 3.47e+00 37 False 84
16 NVP-AUY922 ASG003_XC.P907_24H_M14_NVP-AUY922_1.11uM up 2.15e-10 1.64e-05 3.47e+00 37 False 1158
17 BRD-K12244279 PBIOA015_A549_24H_K04_BRD-K12244279_0.37uM up 2.15e-10 1.64e-05 3.47e+00 37 False 204
18 PRIMA1 MOA001_A549_24H_I19_PRIMA1_10uM up 2.15e-10 1.64e-05 3.47e+00 37 False 218
19 AZ-628 ASG003_A549_48H_J14_AZ-628_1.11uM up 2.15e-10 1.64e-05 3.47e+00 37 False 1618

Table 5: Ranked LINCS L1000 signatures predicted to reverse the uploaded geneset.

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Figure 17: barplot representation depicting the -log10p values of the top l2s2_all reversers. Red bars represent statistically significant results; otherwise gray.

drugseqr_fda

perturbation term pvalueReverse adjPvalueReverse oddsRatioReverse reverserOverlap approved count
0 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid28... 5.96e-02 1 1.58e+00 15 True 110
1 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid40... 1.97e-01 1 1.34e+00 12 True 110
2 bosutinib Bosutinib_FA-10-SN61_batchid16_10uM_24h up 2.07e-01 1 1.37e+00 10 True 8
3 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid6_... 2.86e-01 1 1.23e+00 12 True 110
4 tirbanibulin Tirbanibulin_AD-86-OB87_batchid6_0.1uM_24h up 3.74e-01 1 1.15e+00 11 True 8
5 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid3_... 4.34e-01 1 1.13e+00 7 True 110
6 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid16... 7.22e-01 1 8.27e-01 4 True 110
7 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid44... 8.30e-01 1 7.68e-01 8 True 110
8 temozolomide Temozolomide_BA-92-YC70_batchid20_10uM_24h up 8.31e-01 1 5.72e-01 1 True 4
9 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid23... 9.21e-01 1 6.31e-01 6 True 110

Table 6: Ranked FDA-approved DRUG-seq signatures predicted to reverse the uploaded geneset.

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Figure 18: barplot representation depicting the -log10p values of the top FDA-approved drugseqr_fda reversers. Red bars represent statistically significant results; otherwise gray.

drugseqr_all

perturbation term pvalueReverse adjPvalueReverse oddsRatioReverse reverserOverlap approved count
0 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid28... 5.96e-02 1 1.58e+00 15 True 110
1 cephalochromin Cephalochromin_QA-14-AU91_batchid40_10uM_24h up 1.13e-01 1 1.37e+00 19 False 5
2 24995756 24995756_CE-03-YQ91_batchid16_10uM_24h up 1.20e-01 1 1.49e+00 12 False 6
3 tp-472 TP-472_HB-87-YY34_batchid28_10uM_24h up 1.63e-01 1 1.59e+00 7 False 7
4 _HB-92-PE54_batchid52_10uM_24h up 1.91e-01 1 1.80e+00 4 False 8
5 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid40... 1.97e-01 1 1.34e+00 12 True 110
6 bosutinib Bosutinib_FA-10-SN61_batchid16_10uM_24h up 2.07e-01 1 1.37e+00 10 True 8
7 pik-iii Pik-III_EB-47-BB89_batchid16_10uM_24h up 2.12e-01 1 1.93e+00 3 False 7
8 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid6_... 2.86e-01 1 1.23e+00 12 True 110
9 pi4kiiibeta-in-9 PI4KIIIbeta-IN-9_PD-71-MW24_batchid24_10uM_24h up 3.09e-01 1 1.33e+00 6 False 7
10 tx1-85-1 TX1-85-1_S0-EE-YMWJ_batchid32_10uM_24h up 3.33e-01 1 1.29e+00 6 False 6
11 cathepsin g inhibitor i Cathepsin G Inhibitor I_PD-60-FM93_batchid16_1... 3.63e-01 1 1.20e+00 8 False 7
12 tirbanibulin Tirbanibulin_AD-86-OB87_batchid6_0.1uM_24h up 3.74e-01 1 1.15e+00 11 True 8
13 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid3_... 4.34e-01 1 1.13e+00 7 True 110
14 _BD-11-DV28_batchid32_10uM_24h up 4.76e-01 1 1.12e+00 5 False 104
15 _BD-11-DV28_batchid48_10uM_24h up 4.88e-01 1 1.10e+00 5 False 104
16 _BD-11-DV28_batchid33_10uM_24h up 5.17e-01 1 1.04e+00 8 False 104
17 mefloquine Mefloquine_FA-16-HR75_batchid16_10uM_24h up 5.20e-01 1 1.04e+00 7 False 8
18 _BD-11-DV28_batchid29_10uM_24h up 5.25e-01 1 1.03e+00 10 False 104
19 46184988 46184988_DE-69-QQ25_batchid32_10uM_24h up 5.90e-01 1 9.75e-01 11 False 5

Table 7: Ranked DRUG-seq signatures predicted to reverse the uploaded geneset.

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Figure 19: barplot representation depicting the -log10p values of the top drugseqr_all reversers. Red bars represent statistically significant results; otherwise gray.


cells dmso h rep-vs-cells rsl h rep

l2s2_fda

perturbation term pvalueReverse adjPvalueReverse oddsRatioReverse reverserOverlap approved count
0 trametinib PBIOA004_XC.L10_24H_K06_trametinib_2.22uM up 2.15e-10 1.64e-05 3.47e+00 37 True 1552
1 selumetinib ASG003_XC.P909_24H_E04_selumetinib_10uM up 2.15e-10 1.64e-05 3.47e+00 37 True 2242
2 afatinib ASG003_XC.P914_24H_M20_afatinib_1.11uM up 8.27e-10 3.22e-05 3.37e+00 36 True 2348
3 acyclovir REP.A008_MCF7_24H_E06_acyclovir_0.04uM up 8.27e-10 3.22e-05 3.37e+00 36 True 290
4 selumetinib REP.A015_A375_24H_E19_selumetinib_10uM up 8.27e-10 3.22e-05 3.37e+00 36 True 2242
5 trametinib PBIOA004_XC.R10_24H_K04_trametinib_20uM up 8.27e-10 3.22e-05 3.37e+00 36 True 1552
6 dinoprostone FIBR026_MCLF141SZ_6H_M12_dinoprostone_4uM up 8.27e-10 3.22e-05 3.37e+00 36 True 138
7 selumetinib ASG003_XC.P091_24H_E05_selumetinib_1.11uM up 3.07e-09 7.16e-05 3.27e+00 35 True 2242
8 selumetinib LJP006_A549_24H_M07_selumetinib_10uM up 3.07e-09 7.16e-05 3.27e+00 35 True 2242
9 trametinib ASG003_XC.P911_24H_N18_trametinib_0.12uM up 3.07e-09 7.16e-05 3.27e+00 35 True 1552
10 thioridazine CPC006_HCC515_6H_G23_thioridazine_10uM up 3.07e-09 7.16e-05 3.27e+00 35 True 1444
11 selumetinib LKCP001_A549_24H_J10_selumetinib_10uM up 3.07e-09 7.16e-05 3.27e+00 35 True 2242
12 trametinib PBIOA004_XC.L10_24H_K04_trametinib_20uM up 1.11e-08 1.47e-04 3.17e+00 34 True 1552
13 chlorotrianisene PAC003_U2OS_6H_F14_chlorotrianisene_10uM up 1.11e-08 1.47e-04 3.17e+00 34 True 28
14 trametinib ASG003_XC.P909_24H_N18_trametinib_0.12uM up 1.11e-08 1.47e-04 3.17e+00 34 True 1552
15 trametinib ASG002_NCIH1573_24H_G09_trametinib_0.12uM up 1.11e-08 1.47e-04 3.17e+00 34 True 1552
16 famotidine PAC004_U2OS_6H_B06_famotidine_10uM up 1.11e-08 1.47e-04 3.17e+00 34 True 332
17 trametinib LCP001_MCF10A.WT_3H_D16_trametinib_10uM up 1.11e-08 1.47e-04 3.17e+00 34 True 1552
18 thalidomide CPC006_A549_6H_E14_thalidomide_10uM up 1.11e-08 1.47e-04 3.17e+00 34 True 850
19 dasatinib LJP007_HT29_24H_G14_dasatinib_3.33uM up 1.11e-08 1.47e-04 3.17e+00 34 True 3026

Table 8: Ranked FDA-approved LINCS L1000 signatures predicted to reverse the uploaded geneset.

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Figure 20: barplot representation depicting the -log10p values of the top FDA-approved l2s2_fda reversers. Red bars represent statistically significant results; otherwise gray.

l2s2_all

perturbation term pvalueReverse adjPvalueReverse oddsRatioReverse reverserOverlap approved count
0 PD-0325901 LGR001_XC.L100.L_96H_H06_PD-0325901_0.04uM up 1.57e-13 2.63e-07 3.98e+00 42 False 3630
1 BRD-K85051645 CPC007_MCF7_6H_M06_BRD-K85051645_10uM up 3.10e-12 2.60e-06 3.78e+00 40 False 58
2 BIIB-021 REP.A016_MDAMB231_24H_D22_BIIB-021_0.37uM up 1.31e-11 4.41e-06 3.67e+00 39 False 346
3 PD-0325901 LGR001_XC.L100.L_120H_H01_PD-0325901_10uM up 1.31e-11 4.41e-06 3.67e+00 39 False 3630
4 XL-888 ASG003_XC.P908_24H_L14_XL-888_1.11uM up 1.31e-11 4.41e-06 3.67e+00 39 False 878
5 PD-0325901 LGR001_XC.L100.M_72H_H02_PD-0325901_3.33uM up 5.40e-11 8.24e-06 3.57e+00 38 False 3630
6 XL-888 ASG003_XC.P907_24H_L14_XL-888_1.11uM up 5.40e-11 8.24e-06 3.57e+00 38 False 878
7 PD-0325901 LGR001_XC.L100.M_72H_H05_PD-0325901_0.125uM up 5.40e-11 8.24e-06 3.57e+00 38 False 3630
8 BRD-K82710617 MOA001_A549_24H_G05_BRD-K82710617_10uM up 5.40e-11 8.24e-06 3.57e+00 38 False 16
9 SH3BP5 up XPR014_U251MG.311_96H_E11_SH3BP5 up 5.40e-11 8.24e-06 3.57e+00 38 False 150
10 BRD-K26347562 MOA001_A549_24H_K21_BRD-K26347562_10uM up 5.40e-11 8.24e-06 3.57e+00 38 False 196
11 trametinib PBIOA004_XC.L10_24H_K06_trametinib_2.22uM up 2.15e-10 1.64e-05 3.47e+00 37 True 1552
12 vemurafenib LJP005_MDAMB231_24H_C16_vemurafenib_0.37uM up 2.15e-10 1.64e-05 3.47e+00 37 False 1862
13 BRD-K00824317 PAC004_U2OS_6H_B09_BRD-K00824317_4uM up 2.15e-10 1.64e-05 3.47e+00 37 False 40
14 AZ-628 LJP001_MDAMB231_24H_J12_AZ-628_0.08uM up 2.15e-10 1.64e-05 3.47e+00 37 False 1618
15 TNFRSF1A up XPR028_A549.311_96H_C03_TNFRSF1A up 2.15e-10 1.64e-05 3.47e+00 37 False 84
16 NVP-AUY922 ASG003_XC.P907_24H_M14_NVP-AUY922_1.11uM up 2.15e-10 1.64e-05 3.47e+00 37 False 1158
17 BRD-K12244279 PBIOA015_A549_24H_K04_BRD-K12244279_0.37uM up 2.15e-10 1.64e-05 3.47e+00 37 False 204
18 PRIMA1 MOA001_A549_24H_I19_PRIMA1_10uM up 2.15e-10 1.64e-05 3.47e+00 37 False 218
19 AZ-628 ASG003_A549_48H_J14_AZ-628_1.11uM up 2.15e-10 1.64e-05 3.47e+00 37 False 1618

Table 9: Ranked LINCS L1000 signatures predicted to reverse the uploaded geneset.

No description has been provided for this image

Figure 21: barplot representation depicting the -log10p values of the top l2s2_all reversers. Red bars represent statistically significant results; otherwise gray.

drugseqr_fda

perturbation term pvalueReverse adjPvalueReverse oddsRatioReverse reverserOverlap approved count
0 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid28... 5.96e-02 1 1.58e+00 15 True 110
1 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid40... 1.97e-01 1 1.34e+00 12 True 110
2 bosutinib Bosutinib_FA-10-SN61_batchid16_10uM_24h up 2.07e-01 1 1.37e+00 10 True 8
3 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid6_... 2.86e-01 1 1.23e+00 12 True 110
4 tirbanibulin Tirbanibulin_AD-86-OB87_batchid6_0.1uM_24h up 3.74e-01 1 1.15e+00 11 True 8
5 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid3_... 4.34e-01 1 1.13e+00 7 True 110
6 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid16... 7.22e-01 1 8.27e-01 4 True 110
7 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid44... 8.30e-01 1 7.68e-01 8 True 110
8 temozolomide Temozolomide_BA-92-YC70_batchid20_10uM_24h up 8.31e-01 1 5.72e-01 1 True 4
9 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid23... 9.21e-01 1 6.31e-01 6 True 110

Table 10: Ranked FDA-approved DRUG-seq signatures predicted to reverse the uploaded geneset.

No description has been provided for this image

Figure 22: barplot representation depicting the -log10p values of the top FDA-approved drugseqr_fda reversers. Red bars represent statistically significant results; otherwise gray.

drugseqr_all

perturbation term pvalueReverse adjPvalueReverse oddsRatioReverse reverserOverlap approved count
0 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid28... 5.96e-02 1 1.58e+00 15 True 110
1 cephalochromin Cephalochromin_QA-14-AU91_batchid40_10uM_24h up 1.13e-01 1 1.37e+00 19 False 5
2 24995756 24995756_CE-03-YQ91_batchid16_10uM_24h up 1.20e-01 1 1.49e+00 12 False 6
3 tp-472 TP-472_HB-87-YY34_batchid28_10uM_24h up 1.63e-01 1 1.59e+00 7 False 7
4 _HB-92-PE54_batchid52_10uM_24h up 1.91e-01 1 1.80e+00 4 False 8
5 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid40... 1.97e-01 1 1.34e+00 12 True 110
6 bosutinib Bosutinib_FA-10-SN61_batchid16_10uM_24h up 2.07e-01 1 1.37e+00 10 True 8
7 pik-iii Pik-III_EB-47-BB89_batchid16_10uM_24h up 2.12e-01 1 1.93e+00 3 False 7
8 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid6_... 2.86e-01 1 1.23e+00 12 True 110
9 pi4kiiibeta-in-9 PI4KIIIbeta-IN-9_PD-71-MW24_batchid24_10uM_24h up 3.09e-01 1 1.33e+00 6 False 7
10 tx1-85-1 TX1-85-1_S0-EE-YMWJ_batchid32_10uM_24h up 3.33e-01 1 1.29e+00 6 False 6
11 cathepsin g inhibitor i Cathepsin G Inhibitor I_PD-60-FM93_batchid16_1... 3.63e-01 1 1.20e+00 8 False 7
12 tirbanibulin Tirbanibulin_AD-86-OB87_batchid6_0.1uM_24h up 3.74e-01 1 1.15e+00 11 True 8
13 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid3_... 4.34e-01 1 1.13e+00 7 True 110
14 _BD-11-DV28_batchid32_10uM_24h up 4.76e-01 1 1.12e+00 5 False 104
15 _BD-11-DV28_batchid48_10uM_24h up 4.88e-01 1 1.10e+00 5 False 104
16 _BD-11-DV28_batchid33_10uM_24h up 5.17e-01 1 1.04e+00 8 False 104
17 mefloquine Mefloquine_FA-16-HR75_batchid16_10uM_24h up 5.20e-01 1 1.04e+00 7 False 8
18 _BD-11-DV28_batchid29_10uM_24h up 5.25e-01 1 1.03e+00 10 False 104
19 46184988 46184988_DE-69-QQ25_batchid32_10uM_24h up 5.90e-01 1 9.75e-01 11 False 5

Table 11: Ranked DRUG-seq signatures predicted to reverse the uploaded geneset.

No description has been provided for this image

Figure 23: barplot representation depicting the -log10p values of the top drugseqr_all reversers. Red bars represent statistically significant results; otherwise gray.


Mimicker Results

cells dmso h rep-vs-cells rsl fer h rep

l2s2_fda

perturbation term pvalueMimic adjPvalueMimic oddsRatioMimic mimickerOverlap approved count
0 crizotinib ASG003_XC.P914_24H_I04_crizotinib_10uM up 3.10e-12 5.20e-07 3.78e+00 40 True 1884
1 sonidegib FIBR011_MCLF015CN_6H_E03_sonidegib_4uM up 5.40e-11 5.04e-06 3.57e+00 38 True 502
2 ingenol-mebutate REP.B027_HEK293_24H_D22_ingenol-mebutate_0.08u... 2.15e-10 1.03e-05 3.47e+00 37 True 310
3 dabrafenib ASG002_MKN45_24H_K24_dabrafenib_0.12uM up 2.15e-10 1.03e-05 3.47e+00 37 True 1304
4 sonidegib FIBR010_MCLF123SZ_6H_E03_sonidegib_4uM up 2.15e-10 1.03e-05 3.47e+00 37 True 502
5 dabrafenib ASG003_XC.P091_24H_H18_dabrafenib_0.12uM up 2.15e-10 1.03e-05 3.47e+00 37 True 1304
6 raloxifene ASG003_XC.P904_24H_I13_raloxifene_10uM up 2.15e-10 1.03e-05 3.47e+00 37 True 1452
7 fluphenazine PAC066_U2OS_6H_B24_fluphenazine_20uM up 2.15e-10 1.03e-05 3.47e+00 37 True 750
8 trifluoperazine PAC004_U2OS_6H_A14_trifluoperazine_20uM up 8.27e-10 2.10e-05 3.37e+00 36 True 1388
9 cyt-387 LJP005_A549_24H_P08_CYT-387_3.33uM up 8.27e-10 2.10e-05 3.37e+00 36 True 772
10 fluphenazine PAC001_U2OS_6H_K24_fluphenazine_20uM up 8.27e-10 2.10e-05 3.37e+00 36 True 750
11 ingenol HOG001_A549_24H_B16_ingenol_1.11uM up 8.27e-10 2.10e-05 3.37e+00 36 True 214
12 thioridazine PAC067_U2OS_6H_L01_thioridazine_20uM up 8.27e-10 2.10e-05 3.37e+00 36 True 1444
13 tretinoin FIBR010_MCLF123SZ_6H_B03_tretinoin_4uM up 8.27e-10 2.10e-05 3.37e+00 36 True 988
14 ingenol-mebutate REP.B027_HELA_24H_D20_ingenol-mebutate_0.74uM up 8.27e-10 2.10e-05 3.37e+00 36 True 310
15 trifluoperazine PAC006_U2OS_6H_A14_trifluoperazine_20uM up 8.27e-10 2.10e-05 3.37e+00 36 True 1388
16 ingenol-mebutate REP.B027_HELA_24H_D21_ingenol-mebutate_0.25uM up 3.07e-09 5.37e-05 3.27e+00 35 True 310
17 ingenol-mebutate REP.B027_HELA_24H_D22_ingenol-mebutate_0.08uM up 3.07e-09 5.37e-05 3.27e+00 35 True 310
18 carbamazepine KTOX002_HPTEC_6H_N13_carbamazepine_1000uM up 3.07e-09 5.37e-05 3.27e+00 35 True 638
19 nilotinib LKCP001_A549_24H_G01_nilotinib_10uM up 3.07e-09 5.37e-05 3.27e+00 35 True 1230

Table 12: Ranked FDA-approved LINCS L1000 signatures predicted to mimic the uploaded geneset.

No description has been provided for this image

Figure 24: barplot representation depicting the -log10p values of the top FDA-approved l2s2_fda mimickers. Red bars represent statistically significant results; otherwise gray.

l2s2_all

perturbation term pvalueMimic adjPvalueMimic oddsRatioMimic mimickerOverlap approved count
0 quizartinib ASG003_XC.P915_24H_F10_quizartinib_10uM up 1.00e-17 1.68e-11 4.61e+00 48 False 1482
1 TL-HRAS-61 MOA001_A549_24H_G11_TL-HRAS-61_10uM up 3.38e-14 2.83e-08 4.09e+00 43 False 434
2 CGS-15943 ASG003_XC.P091_24H_K13_CGS-15943_10uM up 1.57e-13 8.78e-08 3.98e+00 42 False 712
3 BRD-K67526586 ERG012_PC3_6H_O17_BRD-K67526586_10uM up 7.09e-13 2.38e-07 3.88e+00 41 False 16
4 KIN-001-220 LJP009_SKL.C_24H_F13_KIN-001-220_10uM up 7.09e-13 2.38e-07 3.88e+00 41 False 650
5 crizotinib ASG003_XC.P914_24H_I04_crizotinib_10uM up 3.10e-12 5.20e-07 3.78e+00 40 True 1884
6 BRD-K68313733 CPC007_HT29_6H_I03_BRD-K68313733_10uM up 3.10e-12 5.20e-07 3.78e+00 40 False 64
7 IL3RA up XPR018_ES2.311_96H_G16_IL3RA up 3.10e-12 5.20e-07 3.78e+00 40 False 40
8 parbendazole MOA001_A549_24H_P04_parbendazole_10uM up 3.10e-12 5.20e-07 3.78e+00 40 False 904
9 fenbendazole MOA001_A549_24H_O03_fenbendazole_10uM up 3.10e-12 5.20e-07 3.78e+00 40 False 126
10 BRD-A15079084 HOG001_A549_6H_G22_BRD-A15079084_0.002uM up 1.31e-11 2.01e-06 3.67e+00 39 False 202
11 PX-12 FIBR027_MCLF130CN_6H_E18_PX-12_4uM up 5.40e-11 5.04e-06 3.57e+00 38 False 508
12 parbendazole MOA001_A549_24H_O04_parbendazole_10uM up 5.40e-11 5.04e-06 3.57e+00 38 False 904
13 calmidazolium CPC014_A549_6H_J20_calmidazolium_10uM up 5.40e-11 5.04e-06 3.57e+00 38 False 174
14 sonidegib FIBR011_MCLF015CN_6H_E03_sonidegib_4uM up 5.40e-11 5.04e-06 3.57e+00 38 True 502
15 BRD-K51556300 CPC019_HT29_6H_P22_BRD-K51556300_10uM up 5.40e-11 5.04e-06 3.57e+00 38 False 82
16 BRD-A15079084 HOG001_A549_6H_G14_BRD-A15079084_10uM up 5.40e-11 5.04e-06 3.57e+00 38 False 202
17 QS-11 FIBR011_MCLF015CN_6H_K12_QS-11_4uM up 5.40e-11 5.04e-06 3.57e+00 38 False 212
18 ingenol-mebutate REP.B027_HEK293_24H_D22_ingenol-mebutate_0.08u... 2.15e-10 1.03e-05 3.47e+00 37 True 310
19 BRD-K56411643 MOA001_A549_24H_C03_BRD-K56411643_10uM up 2.15e-10 1.03e-05 3.47e+00 37 False 178

Table 13: Ranked LINCS L1000 signatures predicted to mimic the uploaded geneset.

No description has been provided for this image

Figure 25: barplot representation depicting the -log10p values of the top l2s2_all mimickers. Red bars represent statistically significant results; otherwise gray.

drugseqr_fda

perturbation term pvalueMimic adjPvalueMimic oddsRatioMimic mimickerOverlap approved count
0 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid6_... 2.02e-06 4.19e-03 2.81e+00 27 True 110
1 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid3_... 4.78e-06 5.72e-03 3.31e+00 20 True 110
2 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid28... 1.20e-05 1.26e-02 2.67e+00 25 True 110
3 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid40... 1.31e-05 1.33e-02 2.72e+00 24 True 110
4 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid23... 3.15e-05 2.30e-02 2.58e+00 24 True 110
5 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid16... 3.31e-05 2.35e-02 3.40e+00 16 True 110
6 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid44... 4.99e-05 3.09e-02 2.44e+00 25 True 110
7 bosutinib Bosutinib_FA-10-SN61_batchid16_10uM_24h up 5.38e-05 3.15e-02 2.78e+00 20 True 8
8 temozolomide Temozolomide_BA-92-YC70_batchid20_10uM_24h up 7.03e-05 3.72e-02 5.42e+00 9 True 4
9 tirbanibulin Tirbanibulin_AD-86-OB87_batchid6_0.1uM_24h up 1.05e-04 4.79e-02 2.44e+00 23 True 8

Table 14: Ranked FDA-approved DRUG-seq signatures predicted to mimic the uploaded geneset.

No description has been provided for this image

Figure 26: barplot representation depicting the -log10p values of the top FDA-approved drugseqr_fda mimickers. Red bars represent statistically significant results; otherwise gray.

drugseqr_all

perturbation term pvalueMimic adjPvalueMimic oddsRatioMimic mimickerOverlap approved count
0 _BD-11-DV28_batchid9_10uM_24h up 2.67e-08 7.02e-04 3.77e+00 25 False 104
1 _GE-53-SM76_batchid35_1uM_24h up 6.97e-08 9.17e-04 4.63e+00 19 False 7
2 11591924 11591924_FB-95-JD99_batchid20_10uM_24h up 2.54e-07 1.79e-03 3.86e+00 21 False 5
3 mefloquine Mefloquine_FA-16-HR75_batchid16_10uM_24h up 3.26e-07 1.79e-03 3.52e+00 23 False 8
4 46184988 46184988_DE-69-QQ25_batchid32_10uM_24h up 3.40e-07 1.79e-03 2.80e+00 31 False 5
5 galeterone Galeterone_BD-36-VB52_batchid20_10uM_24h up 5.24e-07 2.30e-03 5.13e+00 15 False 6
6 pi4kiiibeta-in-9 PI4KIIIbeta-IN-9_PD-71-MW24_batchid24_10uM_24h up 8.35e-07 3.14e-03 4.11e+00 18 False 7
7 staurosporine Staurosporine_AA-58-FJ71_batchid13_0.01uM_24h up 1.24e-06 3.75e-03 2.49e+00 34 False 8
8 tx1-85-1 TX1-85-1_S0-EE-YMWJ_batchid32_10uM_24h up 1.28e-06 3.75e-03 3.98e+00 18 False 6
9 inflachromene Inflachromene_GD-72-XO18_batchid44_10uM_24h up 1.47e-06 3.87e-03 2.00e+01 6 False 6
10 zygosporin a Zygosporin A_BE-42-IC00_batchid40_10uM_24h up 1.78e-06 4.19e-03 2.36e+00 36 False 8
11 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid6_... 2.02e-06 4.19e-03 2.81e+00 27 True 110
12 9807391 9807391_AD-00-WA10_batchid28_10uM_24h up 2.13e-06 4.19e-03 2.00e+00 49 False 6
13 _QC-76-GI57_batchid36_10uM_24h up 2.23e-06 4.19e-03 4.87e+00 14 False 5
14 _BD-11-DV28_batchid32_10uM_24h up 3.25e-06 5.61e-03 3.91e+00 17 False 104
15 _BD-11-DV28_batchid35_10uM_24h up 3.41e-06 5.61e-03 2.88e+00 25 False 104
16 cephalochromin Cephalochromin_QA-14-AU91_batchid40_10uM_24h up 3.84e-06 5.63e-03 2.40e+00 33 False 5
17 imd-0354 Imd-0354_LB-65-SM65_batchid32_10uM_24h up 4.03e-06 5.63e-03 2.85e+00 25 False 8
18 cathepsin g inhibitor i Cathepsin G Inhibitor I_PD-60-FM93_batchid16_1... 4.26e-06 5.63e-03 3.22e+00 21 False 7
19 lly-507 Lly-507_AE-52-NW93_batchid20_10uM_24h up 4.28e-06 5.63e-03 2.18e+00 39 False 4

Table 15: Ranked DRUG-seq signatures predicted to mimic the uploaded geneset.

No description has been provided for this image

Figure 27: barplot representation depicting the -log10p values of the top drugseqr_all mimickers. Red bars represent statistically significant results; otherwise gray.


cells dmso h rep-vs-cells rsl h rep

l2s2_fda

perturbation term pvalueMimic adjPvalueMimic oddsRatioMimic mimickerOverlap approved count
0 crizotinib ASG003_XC.P914_24H_I04_crizotinib_10uM up 3.10e-12 5.20e-07 3.78e+00 40 True 1884
1 sonidegib FIBR011_MCLF015CN_6H_E03_sonidegib_4uM up 5.40e-11 5.04e-06 3.57e+00 38 True 502
2 ingenol-mebutate REP.B027_HEK293_24H_D22_ingenol-mebutate_0.08u... 2.15e-10 1.03e-05 3.47e+00 37 True 310
3 dabrafenib ASG002_MKN45_24H_K24_dabrafenib_0.12uM up 2.15e-10 1.03e-05 3.47e+00 37 True 1304
4 sonidegib FIBR010_MCLF123SZ_6H_E03_sonidegib_4uM up 2.15e-10 1.03e-05 3.47e+00 37 True 502
5 dabrafenib ASG003_XC.P091_24H_H18_dabrafenib_0.12uM up 2.15e-10 1.03e-05 3.47e+00 37 True 1304
6 raloxifene ASG003_XC.P904_24H_I13_raloxifene_10uM up 2.15e-10 1.03e-05 3.47e+00 37 True 1452
7 fluphenazine PAC066_U2OS_6H_B24_fluphenazine_20uM up 2.15e-10 1.03e-05 3.47e+00 37 True 750
8 trifluoperazine PAC004_U2OS_6H_A14_trifluoperazine_20uM up 8.27e-10 2.10e-05 3.37e+00 36 True 1388
9 cyt-387 LJP005_A549_24H_P08_CYT-387_3.33uM up 8.27e-10 2.10e-05 3.37e+00 36 True 772
10 fluphenazine PAC001_U2OS_6H_K24_fluphenazine_20uM up 8.27e-10 2.10e-05 3.37e+00 36 True 750
11 ingenol HOG001_A549_24H_B16_ingenol_1.11uM up 8.27e-10 2.10e-05 3.37e+00 36 True 214
12 thioridazine PAC067_U2OS_6H_L01_thioridazine_20uM up 8.27e-10 2.10e-05 3.37e+00 36 True 1444
13 tretinoin FIBR010_MCLF123SZ_6H_B03_tretinoin_4uM up 8.27e-10 2.10e-05 3.37e+00 36 True 988
14 ingenol-mebutate REP.B027_HELA_24H_D20_ingenol-mebutate_0.74uM up 8.27e-10 2.10e-05 3.37e+00 36 True 310
15 trifluoperazine PAC006_U2OS_6H_A14_trifluoperazine_20uM up 8.27e-10 2.10e-05 3.37e+00 36 True 1388
16 ingenol-mebutate REP.B027_HELA_24H_D21_ingenol-mebutate_0.25uM up 3.07e-09 5.37e-05 3.27e+00 35 True 310
17 ingenol-mebutate REP.B027_HELA_24H_D22_ingenol-mebutate_0.08uM up 3.07e-09 5.37e-05 3.27e+00 35 True 310
18 carbamazepine KTOX002_HPTEC_6H_N13_carbamazepine_1000uM up 3.07e-09 5.37e-05 3.27e+00 35 True 638
19 nilotinib LKCP001_A549_24H_G01_nilotinib_10uM up 3.07e-09 5.37e-05 3.27e+00 35 True 1230

Table 16: Ranked FDA-approved LINCS L1000 signatures predicted to mimic the uploaded geneset.

No description has been provided for this image

Figure 28: barplot representation depicting the -log10p values of the top FDA-approved l2s2_fda mimickers. Red bars represent statistically significant results; otherwise gray.

l2s2_all

perturbation term pvalueMimic adjPvalueMimic oddsRatioMimic mimickerOverlap approved count
0 quizartinib ASG003_XC.P915_24H_F10_quizartinib_10uM up 1.00e-17 1.68e-11 4.61e+00 48 False 1482
1 TL-HRAS-61 MOA001_A549_24H_G11_TL-HRAS-61_10uM up 3.38e-14 2.83e-08 4.09e+00 43 False 434
2 CGS-15943 ASG003_XC.P091_24H_K13_CGS-15943_10uM up 1.57e-13 8.78e-08 3.98e+00 42 False 712
3 BRD-K67526586 ERG012_PC3_6H_O17_BRD-K67526586_10uM up 7.09e-13 2.38e-07 3.88e+00 41 False 16
4 KIN-001-220 LJP009_SKL.C_24H_F13_KIN-001-220_10uM up 7.09e-13 2.38e-07 3.88e+00 41 False 650
5 crizotinib ASG003_XC.P914_24H_I04_crizotinib_10uM up 3.10e-12 5.20e-07 3.78e+00 40 True 1884
6 BRD-K68313733 CPC007_HT29_6H_I03_BRD-K68313733_10uM up 3.10e-12 5.20e-07 3.78e+00 40 False 64
7 IL3RA up XPR018_ES2.311_96H_G16_IL3RA up 3.10e-12 5.20e-07 3.78e+00 40 False 40
8 parbendazole MOA001_A549_24H_P04_parbendazole_10uM up 3.10e-12 5.20e-07 3.78e+00 40 False 904
9 fenbendazole MOA001_A549_24H_O03_fenbendazole_10uM up 3.10e-12 5.20e-07 3.78e+00 40 False 126
10 BRD-A15079084 HOG001_A549_6H_G22_BRD-A15079084_0.002uM up 1.31e-11 2.01e-06 3.67e+00 39 False 202
11 PX-12 FIBR027_MCLF130CN_6H_E18_PX-12_4uM up 5.40e-11 5.04e-06 3.57e+00 38 False 508
12 parbendazole MOA001_A549_24H_O04_parbendazole_10uM up 5.40e-11 5.04e-06 3.57e+00 38 False 904
13 calmidazolium CPC014_A549_6H_J20_calmidazolium_10uM up 5.40e-11 5.04e-06 3.57e+00 38 False 174
14 sonidegib FIBR011_MCLF015CN_6H_E03_sonidegib_4uM up 5.40e-11 5.04e-06 3.57e+00 38 True 502
15 BRD-K51556300 CPC019_HT29_6H_P22_BRD-K51556300_10uM up 5.40e-11 5.04e-06 3.57e+00 38 False 82
16 BRD-A15079084 HOG001_A549_6H_G14_BRD-A15079084_10uM up 5.40e-11 5.04e-06 3.57e+00 38 False 202
17 QS-11 FIBR011_MCLF015CN_6H_K12_QS-11_4uM up 5.40e-11 5.04e-06 3.57e+00 38 False 212
18 ingenol-mebutate REP.B027_HEK293_24H_D22_ingenol-mebutate_0.08u... 2.15e-10 1.03e-05 3.47e+00 37 True 310
19 BRD-K56411643 MOA001_A549_24H_C03_BRD-K56411643_10uM up 2.15e-10 1.03e-05 3.47e+00 37 False 178

Table 17: Ranked LINCS L1000 signatures predicted to mimic the uploaded geneset.

No description has been provided for this image

Figure 29: barplot representation depicting the -log10p values of the top l2s2_all mimickers. Red bars represent statistically significant results; otherwise gray.

drugseqr_fda

perturbation term pvalueMimic adjPvalueMimic oddsRatioMimic mimickerOverlap approved count
0 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid6_... 2.02e-06 4.19e-03 2.81e+00 27 True 110
1 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid3_... 4.78e-06 5.72e-03 3.31e+00 20 True 110
2 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid28... 1.20e-05 1.26e-02 2.67e+00 25 True 110
3 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid40... 1.31e-05 1.33e-02 2.72e+00 24 True 110
4 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid23... 3.15e-05 2.30e-02 2.58e+00 24 True 110
5 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid16... 3.31e-05 2.35e-02 3.40e+00 16 True 110
6 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid44... 4.99e-05 3.09e-02 2.44e+00 25 True 110
7 bosutinib Bosutinib_FA-10-SN61_batchid16_10uM_24h up 5.38e-05 3.15e-02 2.78e+00 20 True 8
8 temozolomide Temozolomide_BA-92-YC70_batchid20_10uM_24h up 7.03e-05 3.72e-02 5.42e+00 9 True 4
9 tirbanibulin Tirbanibulin_AD-86-OB87_batchid6_0.1uM_24h up 1.05e-04 4.79e-02 2.44e+00 23 True 8

Table 18: Ranked FDA-approved DRUG-seq signatures predicted to mimic the uploaded geneset.

No description has been provided for this image

Figure 30: barplot representation depicting the -log10p values of the top FDA-approved drugseqr_fda mimickers. Red bars represent statistically significant results; otherwise gray.

drugseqr_all

perturbation term pvalueMimic adjPvalueMimic oddsRatioMimic mimickerOverlap approved count
0 _BD-11-DV28_batchid9_10uM_24h up 2.67e-08 7.02e-04 3.77e+00 25 False 104
1 _GE-53-SM76_batchid35_1uM_24h up 6.97e-08 9.17e-04 4.63e+00 19 False 7
2 11591924 11591924_FB-95-JD99_batchid20_10uM_24h up 2.54e-07 1.79e-03 3.86e+00 21 False 5
3 mefloquine Mefloquine_FA-16-HR75_batchid16_10uM_24h up 3.26e-07 1.79e-03 3.52e+00 23 False 8
4 46184988 46184988_DE-69-QQ25_batchid32_10uM_24h up 3.40e-07 1.79e-03 2.80e+00 31 False 5
5 galeterone Galeterone_BD-36-VB52_batchid20_10uM_24h up 5.24e-07 2.30e-03 5.13e+00 15 False 6
6 pi4kiiibeta-in-9 PI4KIIIbeta-IN-9_PD-71-MW24_batchid24_10uM_24h up 8.35e-07 3.14e-03 4.11e+00 18 False 7
7 staurosporine Staurosporine_AA-58-FJ71_batchid13_0.01uM_24h up 1.24e-06 3.75e-03 2.49e+00 34 False 8
8 tx1-85-1 TX1-85-1_S0-EE-YMWJ_batchid32_10uM_24h up 1.28e-06 3.75e-03 3.98e+00 18 False 6
9 inflachromene Inflachromene_GD-72-XO18_batchid44_10uM_24h up 1.47e-06 3.87e-03 2.00e+01 6 False 6
10 zygosporin a Zygosporin A_BE-42-IC00_batchid40_10uM_24h up 1.78e-06 4.19e-03 2.36e+00 36 False 8
11 omacetaxine mepesuccinate Omacetaxine Mepesuccinate_EA-18-FP00_batchid6_... 2.02e-06 4.19e-03 2.81e+00 27 True 110
12 9807391 9807391_AD-00-WA10_batchid28_10uM_24h up 2.13e-06 4.19e-03 2.00e+00 49 False 6
13 _QC-76-GI57_batchid36_10uM_24h up 2.23e-06 4.19e-03 4.87e+00 14 False 5
14 _BD-11-DV28_batchid32_10uM_24h up 3.25e-06 5.61e-03 3.91e+00 17 False 104
15 _BD-11-DV28_batchid35_10uM_24h up 3.41e-06 5.61e-03 2.88e+00 25 False 104
16 cephalochromin Cephalochromin_QA-14-AU91_batchid40_10uM_24h up 3.84e-06 5.63e-03 2.40e+00 33 False 5
17 imd-0354 Imd-0354_LB-65-SM65_batchid32_10uM_24h up 4.03e-06 5.63e-03 2.85e+00 25 False 8
18 cathepsin g inhibitor i Cathepsin G Inhibitor I_PD-60-FM93_batchid16_1... 4.26e-06 5.63e-03 3.22e+00 21 False 7
19 lly-507 Lly-507_AE-52-NW93_batchid20_10uM_24h up 4.28e-06 5.63e-03 2.18e+00 39 False 4

Table 19: Ranked DRUG-seq signatures predicted to mimic the uploaded geneset.

No description has been provided for this image

Figure 31: barplot representation depicting the -log10p values of the top drugseqr_all mimickers. Red bars represent statistically significant results; otherwise gray.


References

[1] Tai, F., Zhai, R., Ding, K., Zhang, Y., Yang, H., Li, H., Wang, Q., Cao, Z., Ge, C., Fu, H., Xiao, F., & Zheng, X. (2024). Long non‑coding RNA lung cancer‑associated transcript 1 regulates ferroptosis via microRNA‑34a‑5p‑mediated GTP cyclohydrolase 1 downregulation in lung cancer cells.. Int J Oncol, 64(6), .

[2] McInnes L, Healy J, Saul N, Großberger L. UMAP: Uniform manifold approximation and projection. Journal of Open Source Software. 2018;3(29):861. doi:10.21105/joss.00861

[3] Clark NR, Ma’ayan A. Introduction to statistical methods to analyze large data sets: Principal Components Analysis. Science Signaling. 2011;4(190):tr3-tr3. doi:10.1126/scisignal.2001967

[4] van der Maaten L, Hinton G. Visualizing Data using t-SNE. Journal of Machine Learning Research. 2008;9(86):2579-2605.

[5] Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, Clark NR, Ma'ayan A. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. 2013;128(14)

[6] Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, Koplev S, Jenkins SL, Jagodnik KM, Lachmann A, McDermott MG, Monteiro CD, Gundersen GW, Ma'ayan A. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Research. 2016; gkw377.

[7] Xie Z, Bailey A, Kuleshov MV, Clarke DJB., Evangelista JE, Jenkins SL, Lachmann A, Wojciechowicz ML, Kropiwnicki E, Jagodnik KM, Jeon M, & Ma’ayan A. Gene set knowledge discovery with Enrichr. Current Protocols, 1, e90. 2021. doi: 10.1002/cpz1.90

[8] Keenan AB, Torre D, Lachmann A, Leong AK, Wojciechowicz M, Utti V, Jagodnik K, Kropiwnicki E, Wang Z, Ma'ayan A (2019) ChEA3: transcription factor enrichment analysis by orthogonal omics integration. Nucleic Acids Research. doi: 10.1093/nar/gkz446

[9] Marino GB, Evangelista JE, Clarke DJB, Ma’ayan A. L2S2: chemical perturbation and CRISPR KO LINCS L1000 signature search engine. Nucleic Acids Res. 2025; gkaf373. doi:10.1093/nar/gkaf373

[10] Li J, Ho DJ, Henault M, et al. DRUG-seq Provides Unbiased Biological Activity Readouts for Neuroscience Drug Discovery. ACS Chem Biol. 2022;17(6):1401-1414. doi:10.1021/acschembio.1c00920

[11] Lachmann A, Torre D, Keenan AB, Jagodnik KM, Lee HJ, Wang L, Silverstein MC, Ma'ayan A. Massive mining of publicly available RNA-seq data from human and mouse. Nature Communications 9. Article number: 1366 (2018), doi: 10.1038/s41467-018-03751-6.

[12] Bray, N., Pimentel, H., Melsted, P. et al. Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol 34, 525–527 (2016). https://doi.org/10.1038/nbt.3519

[13] Fernandez, N. F. et al. Clustergrammer, a web-based heatmap visualization and analysis tool for high-dimensional biological data. Sci. Data 4:170151 doi: 10.1038/sdata.2017.151 (2017).

[14] Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015 Apr 20;43(7):e47. doi: 10.1093/nar/gkv007.

[15] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, Haw R, Jassal B, Matthews L, May B, Petryszak R, Ragueneau E, Rothfels K, Sevilla C, Shamovsky V, Stephan R, Tiwari K, Varusai T, Weiser J, Wright A, Wu G, Stein L, Hermjakob H, D’Eustachio P. The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research. 2024. doi: 10.1093/nar/gkad1025.

[16] Eppig JT, Smith CL, Blake JA, Ringwald M, Kadin JA, Richardson JE, Bult CJ. Mouse Genome Informatics (MGI): Resources for Mining Mouse Genetic, Genomic, and Biological Data in Support of Primary and Translational Research. Methods Mol Biol. 2017;1488:47-73. doi: 10.1007/978-1-4939-6427-7_3.

[17] Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000 May;25(1):25-9. doi: 10.1038/75556.

[18] Cerezo M, Sollis E, Ji Y, et al. The NHGRI-EBI GWAS Catalog: standards for reusability, sustainability and diversity. Nucleic Acids Res. 2025;53(D1):D998-D1005. doi:10.1093/nar/gkae1070

[19] Kanehisa M, Furumichi M, Sato Y, Matsuura Y, Ishiguro-Watanabe M. KEGG: biological systems database as a model of the real world. Nucleic Acids Res. 2025;53(D1):D672-D677. doi:10.1093/nar/gkae909

[20] Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27-30. doi:10.1093/nar/28.1.27

[21] Kanehisa M. Toward understanding the origin and evolution of cellular organisms. Protein Sci. 2019;28(11):1947-1951. doi:10.1002/pro.3715

[22] Pico AR, Kelder T, van Iersel MP, Hanspers K, Conklin BR, Evelo C. WikiPathways: pathway editing for the people. PLoS Biol. 2008 Jul 22;6(7):e184. doi: 10.1371/journal.pbio.0060184.

[23] GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013 Jun;45(6):580-5. doi: 10.1038/ng.2653.

[24] ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57-74. doi:10.1038/nature11247

[25] Luo Y, Hitz BC, Gabdank I, et al. New developments on the Encyclopedia of DNA Elements (ENCODE) data portal. Nucleic Acids Res. 2020;48(D1):D882-D889. doi:10.1093/nar/gkz1062

[26] Hammal F, de Langen P, Bergon A, Lopez F, Ballester B. ReMap 2022: a database of Human, Mouse, Drosophila and Arabidopsis regulatory regions from an integrative analysis of DNA-binding sequencing experiments. Nucleic Acids Res. 2022;50(D1):D316-D325. doi:10.1093/nar/gkab996